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Normal hemostasis and coagulation
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- 2. DefinitionDefinition Normal hemostasis Tightly regulatedprocesses Maintain blood in a fluid state in normal vessels Thrombosis Pathologic counterpartPathologic counterpart Thrombus within intact vessels Three components: 1. 10/9/2016 2
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- 4. EndotheliumEndothelium Key players inthe regulation of homeostasis Have Anti- and prothrombotic activities ; Thrombus formation Propagation, or Dissolution occursDissolution occurs exhibit Antithrombotic activity: 10/9/2016 4
- 5. Mediated by; Physical Barrier Prostacyclin(PGI2) AntiAntithromboticthrombotic activityactivity Prostacyclin (PGI2) Nitric oxide (NO) ADPase inhibits platelet aggregation 10/9/2016 5
- 6. These effects aremediated by: Endothelial membrane-associated They are cofactors Enhance plasma protein antithrombin III activityEnhance plasma protein antithrombin III activity modulates the activity of Thrombin Cell surface protein Directly inhibits tissue factor,VIIa & Xa 10/9/2016 6
- 7. 3. Fibrinolytic properties3.Fibrinolytic properties Endothelial cells synthesize: Tissue-type plasminogen activator (t-PA) A protease that cleaves plasminogen to form plasmin PlasminPlasmin, in turn, cleaves fibrin to degradePlasminPlasmin, in turn, cleaves fibrin to degrade thrombi 10/9/2016 7
- 8. Exposure & contactof platelets to ECM Adhesion mediated by vWF Endothelial release of tissue factor Catalytic function factors IXa and Xa Plasminogen activator inhibitors (PAIs) Limit fibrinolysis & favor thrombosis 10/9/2016 8
- 9. In summaryIn summary Intact,nonactivated endothelial cells Antithrombotic Endothelial injury or activation Prothrombotic 10/9/2016 9
- 10. PlateletsPlatelets Disc-shaped AnucleateAnucleate cell fragments 2-3ꭒm in diameter 8-10 days of half-life Originate from MEGAkaryocytesMEGAkaryocytesOriginate from MEGAkaryocytesMEGAkaryocytes Play a critical role in normal hemostasishemostasis vascular defects Provide a surface for activated coagulation factors Contain 2 types of cytoplasmic granules 10/9/2016 10
- 11. P-selectin Fibrinogen Fibronectin, Factors V andVIII Platelet factor 4 PDGF ADP ATP Calcium Histamine Serotonin Epinephrine 10/9/2016 11 PDGF TGF-β Epinephrine
- 12. Normal HemostasisNormal Hemostasis •general sequence of events in hemostasis 1.Transient arteriolar vasoconstriction Mediated by: Reflex Neurogenic mechanisms Myogenic reflex contraction, andMyogenic reflex contraction, and Endothelin 10/9/2016 12
- 13. 2. Primary hemostasis Endothelialinjury exposes HTSECM, Patelet adherence and activation Dramatic shape changeDramatic shape change Release of secretory granules Recruit additional platelets (aggregation) to form a hemostatic plug
- 14. Platelet adhesionPlatelet adhesion Viainteractions with vWF Other components of the ECM (e.g., fibronectin) 10/9/2016 14
- 15. Degranulation Importance Ca+2Ca+2Ca+2Ca+2 is requiredin the coagulation cascade ADPADPADPADP is a potent platelet aggregator Platelet activation negatively chargedPlatelet activation negatively charged phospholipids on their surfaces Bind calcium and serve as critical nucleation sites 10/9/2016 15
- 16. Follows adhesion andgranule release • ADP • Noncleaved fibrinogen • TxA2 amplifies platelet aggregation primaryprimary hemostatic plughemostatic plug Aggregation is reversibleAggregation is reversible 10/9/2016 16
- 17. 3. Secondary Hemostasis (factorIII or thromboplastin)(factor III or thromboplastin) Membrane-bound procoagulant glycoprotein synthesized by endothelial cells Exposed at the site of injury With factor VII , in vivo initiator of the coagulationWith factor VII , in vivo initiator of the coagulation cascade Thrombin generation Cleavage of fibrinogen into insoluble fibrin Creation a fibrin meshwork Further platelet recruitment and activation 10/9/2016 17
- 18. Coagulation CascadeCoagulation Cascade The3rd arm of the hemostatic process Amplifying series of enzymatic conversions Each step proteolytically cleaves an inactive proenzyme ThrombinThrombin formation is the targetThrombinThrombin formation is the target 10/9/2016 18
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- 21. Each reaction inthe pathway results from interaction of •• EnzymeEnzyme Activated coagulation factor •• SubstrateSubstrate proenzyme coagulation factor •••• CofactorCofactor Reaction accelerator Assembled on a phospholipid surface and Held together by calcium ions 10/9/2016 21